1. Field of the Invention
The present invention relates to novel compounds useful as diagnostic agents for pancreatic exocrine function and their use.
2. Background of the Invention
“Pancreatic exocrine function tests” are useful for the diagnosis of pancreatic diseases such as chronic and acute pancreatitis and pancreatic cancer. They are also useful to assess the condition and prognosis of patients and to control the medication: The general descriptions are found in Arvanitakis and Cooke, Gastroenterology, 74:932 (1978); Niederau and Grendell, Gastroenterology, 88:1973 (1985); Goldberg, Bull. Mol. Biol. Med., 15:1 (1990); Lankisch, Int. J. Pancreatology, 14:9 (1993); Bank and Chow, Gastroenterologist, 2:224 (1994); and Steer et al., New Eng. J. Med., 332:1482 (1995).
At present, “Gold standard” of the pancreatic exocrine function test involves inserting a tube through the mouth to the duodenum to collect the duodenal juice. Now, the secretin test is generally utilized wherein secretin is intravenously administered to stimulate the secretion of the pancreatic juice prior to the collection. This method is highly accurate since the amount and components of the pancreatic juice are directly analyzed. However, this method can not be used repeatedly or used for screening because of the very strong stress caused on the subjects. It is available at only a relatively small number of medical centers having highly skilled physicians. Further, since this method requires fluoroscopic tube placement during the collection of the duodenal juice, there is the problem of X ray exposure.
On the other hand, a test for quantifying pancreatic exocrine enzymes from the pancreas into the blood is clinically employed for screening pancreatic diseases (The Merck Manual 16th edition). However, the increase of the pancreatic exocrine enzymes in the blood is only observed at the initial stage of acute pancreatitis or at the recrudescent stage of chronic pancreatitis and does not always reflect the ability of the pancreas to secrete pancreatic exocrine enzymes. Further, the increase of pancreatic exocrine enzymes in the blood may sometimes not be detected due to serum turbidity in pancreatitis accompanied by hyperlipemia.
Accordingly, simple methods which require no insertion of a tube are utilized for repetition and screening tests. One of them is the pancreolauryl test (PLT) wherein a synthetic substrate FDL (fluorescein diraulate, dilaurylfluorescein) for cholesterol ester hydrolase, esterase, secreted from the pancreas is orally administered and urine is accumulated for 10 hours followed by measuring the amount of a degradation product fluorescein excreted into the urine: U.S. Pat. No. 3,917,812; Barry et al., Lancet (1982) October 2, p. 742; Scharpe and Iliano, Clin. Chem., 33:5 (1987). However, this method requires a long time to carry out the test and therefore can not often be performed on outpatients and is not suitable in physical examinations.
Under these circumstances, there is a need for the development of a simple method for testing the pancreatic exocrine function which imparts low stress on subjects and gives accurate results soon.
On the one hand, the 13C-breath test wherein a 13C-labeled starch is administered has been recently considered to be employed in the test for the pancreatic exocrine function: Hiele et al., Gastroenterology, 96:503 (1989); Dewit et al., Pediatric Res., 32:45 (1992); and Z. Gastroenterol., 35:187 (1997). In the enteric tract, starch is degraded efficiently to glucose by the cleavage at any internal α-1,4 glucoside linkage with α-amylase secreted from the pancreas and by the action of enzymes such as α-glucosidase (maltase) of mucosal epithelial cells of the small intestine and absorbed: Essentials of Human Metabolism, 2nd ed., W. C. McMurray, Harper & Row Publishers, NY. The 13C-breath test wherein a 13C-labeled starch is administered utilizes the phenomenon that after the 13C-labeled starch is degraded in the digestive tract, it is absorbed and decarboxylated by metabolic action in the body to generate 13CO2 which is excreted into the breath, and it is a safe and simple method. However, any 13C-labeled oligosaccharide or polysaccharide other than 13C-labeled starch has not yet been studied.
Since there is an α-glucosidase (maltase) in mucosal epithelial cells of the small intestine, which cleaves a non-reducing terminal α-1,4-glucoside linkage (Enzyme Handbook, Springer-Verlag, Berlin), starch is degraded into glucose sequentially from the non-reducing terminal and absorbed only by the action of enzymes such as the α-glucosidase (maltase), even without the action of α-amylase. Thus, starch is subject to the action of a non-pancreatic-exocrine enzyme α-glucosidase (maltase) of mucosal epithelial cells of the small intestine and therefore the 13C-labeled starch breath test does not reflect the pancreatic exocrine function only. Accordingly, it would be more preferred if a substrate compound specific for α-amylase in the digestive tract is selected.
Accordingly, an object of the present invention is to provide a diagnostic agent for pancreatic exocrine function which leads to a test for the pancreatic exocrine function imparting low stress on subjects and yields the results in a short period of time.
It is another object of the present invention to provide a diagnostic agent for pancreatic exocrine function which is specific to the α-amylase secretion ability.
It is a further object of the present invention to provide a novel compound usable in the pancreatic exocrine function test.